| First Author | Shen J | Year | 2021 |
| Journal | Front Neurosci | Volume | 15 |
| Pages | 715222 | PubMed ID | 34675764 |
| Mgi Jnum | J:312677 | Mgi Id | MGI:6786030 |
| Doi | 10.3389/fnins.2021.715222 | Citation | Shen J, et al. (2021) Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2. Front Neurosci 15:715222 |
| abstractText | Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1alpha and Hif2alpha expression; inhibition of Hif2alpha rescues Irp2 ablation-induced mitochondrial dysfunction; and inhibition of Hif1alpha suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1alpha and Hif2alpha are also elevated in vivo and play a similar role in neurological disorder of Irp2 (-/-) mice. In this study, we confirmed the upregulation of Hif2alpha, not Hif1alpha, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2 (-/-) mice. Consistent with this observation, inhibition of Hif2alpha by PT-2385, not Hif1alpha by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) was reversed. Our results indicate that Irp2 depletion-induced Hif2alpha is, in vivo, in charge of the switch between OXPHOS and glycolysis, suggesting that, for the first time to our knowledge, Hif2alpha is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome. |
